JPH08231398A - Lyophilized preparation - Google Patents

Abstract

PURPOSE: To obtain a lyophilized preparation containing a carbapenem antibiotic (salt) and plural kinds of saccharides, suitable for being dissolved in a solvent to prepare an injection solution, and dissolved in the solvent when used. CONSTITUTION: This preparation contains (A) a carbapenem antibiotic (salt) of formula [R<1> is a lower alkyl, a (protected) hydroxy lower alkyl; R<2> is H, a lower alkyl; R<3> is a (esterified) carboxyl; R<4> , R<9> , R<10> are an amino-protecting group, H, a lower alkyl; R<5> , R<6> are H, OH, a lower alkyl, etc.; R<7> , R<8> are H, a lower alkyl, etc.; Z is a single bond, O, S, etc.; m, n are 0-6], and (B) plural kinds of saccharides comprising inositol, mannitol, etc. The component A includes (1R, 5S, 6S, 8R, 2'S, 4'S)-2- [2-((4-(2S)-5-amino-2-hydroxypentanoyl) piperazin-1-yl)carbonyl)pyrrolidin-4-yl]thio}-6-(1-hydroxyethyl)-1- methylcarbapenem-3-carboxylic acid (salt).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a lyophilized preparation containing a carbapenem antibiotic, more specifically, it contains a carbapenem antibiotic as an active ingredient and is dissolved in a solvent to prepare an injection solution. The present invention relates to a freeze-dried preparation that is suitable for preparation and that is dissolved before use.

[0002]

2. Description of the Related Art Carbapenem antibiotics are generally administered parenterally and intravenously by injection or drip in use. Solution formulations and lyophilized formulations filled in vials are clinically provided as formulation forms suitable for such administration forms. A lyophilized formulation is a formulation in which a predetermined solvent such as distilled water for injection is added to a vial before use to prepare a solution, and long-term storage in a solution state can be avoided, so a formulation with improved stability is provided. There is an advantage that you can. However, the carbapenem antibiotics are substances that are likely to be chemically decomposed during storage, and there is a problem in that a sufficiently stable preparation cannot be provided by the freeze-drying method which has been widely used in the past.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention An object of the present invention is to provide a stable lyophilized preparation containing a carbapenem antibiotic as an active ingredient. As a result of diligent efforts to solve the above problems, the present inventor has found that a freeze-dried preparation containing two or more saccharides in a carbapenem antibiotic is extremely stable even after long-term storage and is an active ingredient. It has been found that the degradation of certain carbapenem antibiotics rarely occurs. The present invention has been completed based on the above findings.

That is, the present invention provides a freeze-dried preparation containing a carbapenem antibiotic or a salt thereof and two or more kinds of sugars. According to a preferred embodiment of the present invention, there is provided the above-mentioned freeze-dried preparation further containing an inorganic salt; and the above-mentioned freeze-dried preparation wherein the sugars are inositol and mannitol. Further, according to another aspect of the present invention, there is provided a method for producing a freeze-dried preparation, which comprises freeze-drying an aqueous solution of a carbapenem antibiotic or a salt thereof in the presence of two or more kinds of sugars.

The freeze-dried preparation of the present invention is characterized by containing a carbapenem antibiotic or a salt thereof and two or more kinds of sugars. The carbapenem antibiotic which is an active ingredient of the freeze-dried preparation of the present invention is not particularly limited, and any compound having a carbapenem skeleton may be used. As the carbapenem antibiotic, in addition to the compound in a free form, physiologically and pharmaceutically acceptable salts can be used, and examples thereof include acid addition salts such as hydrochloride, sulfate, and paratoluenesulfonate. Further, base addition salts such as alkali metal salts, alkaline earth metal salts, ammonium salts and organic amine salts can be used.

Carbapenem antibiotics suitable for the present invention have the following formula:

Embedded image [R ¹ represents a lower alkyl group or a hydroxy lower alkyl group which may have a protecting group; R ² represents a hydrogen atom or a lower alkyl group; R ³ represents a carboxyl group which may be esterified; R ⁴ represents an amino-protecting group, a hydrogen atom or a lower alkyl group; R ⁵ and R ⁶ each independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a hydroxy lower alkyl group or a halogen atom, and further R ⁵ and R ⁶ may combine with each other to form an alkylene group having 2 to 6 carbon atoms; R ⁷ is a hydrogen atom, a lower alkyl group, a carboxyl group, a carbamoyl group, a carboxyl group which may have a protecting group or a partial structure : -CONR ⁷¹ R ⁷² (R ⁷¹ and R ⁷² each independently represent a hydrogen atom or a lower alkyl group); R ⁸ represents a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group. Represents a kill group, and additionally R ⁷ and R ⁸
May together form an alkylene group having 2 to 6 carbon atoms; R ⁹ and R ¹⁰ each independently represent a protecting group for an amino group, a hydrogen atom or a lower alkyl group, and Z is a single bond or oxygen. Atom, sulfur atom, or partial structure: -CR ¹¹ R ^{12
-, -NR 13 CO -, -} CONR 14 or -NR ^15, - (R ¹¹ and
R ^12's each independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a hydroxy lower alkyl group or a halogen atom, and R ¹¹ and R ¹² together form a carbon number of 2 to 6
R ¹³ and R ¹⁴ each independently represent a hydrogen atom or a lower alkyl group,
¹⁵ represents an amino-protecting group, a hydrogen atom or a lower alkyl group); m and n each independently represent an integer of 0 to 6], and carbapenem antibiotics and salts thereof. it can.

Among the above-mentioned preferred carbapenem antibiotics, the above-mentioned compounds wherein R ¹ is a 1-hydroxyethyl group or salts thereof; 6S, 8R-6- (1-hydroxyethyl) carbapenem derivatives or salts thereof; 1R, 5S , 6S, 8R-6- (1-hydroxyethyl) -1-methylcarbapenem derivative or a salt thereof is more preferable, and a particularly preferable compound is (1R, 5S, 6S, 8R, 2 ′).
S, 4'S) -2-((2-((4-((2S) -5-amino-2-hydroxypentanoyl) piperazin-1-yl) carbonyl) pyrrolidin-4-yl) thio) -6- ( 1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid or a salt thereof, or (1
R, 5S, 6S, 8R, 2'S, 4'S) -2- (2- (4- (2- (2-aminoethoxy))
Acetyl) piperazin-1-yl) carbonylpyrrolidine
-4-yl) thio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid or a salt thereof, and the most preferred compound is (1R, 5S, 6S, 8R, 2'S, 4'S) -2-((2-((4-
((2S) -5-Amino-2-hydroxypentanoyl) piperazin-1-yl) carbonyl) pyrrolidin-4-yl) thio) -6
-(1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid hydrochloride, which is a compound represented by the following structural formula.

[0008]

Embedded image The saccharide used in the present invention is not particularly limited, for example,
At least two or more kinds of sugars can be selected from sugars such as maltose, inositol, mannitol, lactose, sucrose, glucose and maltotriose and used in combination. Of these, a combination of inositol and maltose is preferable. The addition amount of these saccharides is not particularly limited, but for example, 50 mg of each saccharide can be added to 500 mg of carbapenem antibiotic.
It can be used in the above proportions, preferably 50-500 mg
, And more preferably 100 to 300 mg.

When an inorganic salt is added in addition to the above-mentioned two or more saccharides, the storage stability of the freeze-dried preparation may be further improved. Therefore, a freeze-dried preparation further containing an inorganic salt is a preferred embodiment of the present invention. is there. Examples of inorganic salts include sodium chloride, potassium chloride, calcium chloride,
Water-soluble salts such as potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate and potassium carbonate can be used. One of these inorganic salts may be added, or two or more thereof may be used in combination. Of these inorganic salts, sodium chloride is preferably used. The addition amount of these inorganic salts is not particularly limited, but it can be used in a ratio of 20 mg or more per 500 mg of carbapenem antibiotic, preferably 30 to 300 mg, more preferably 40 to
It may be used at a ratio of 100 mg.

The freeze-dried preparation of the present invention is prepared by adding a carbapenem antibiotic-containing freeze-dried product produced by a freeze-drying method generally used in the art, to which two or more kinds of sugars and, if necessary, inorganic salts are added. It can be produced by mixing. The sugars and inorganic salts to be added may be added separately, or a mixture containing them may be prepared in advance and added. Further, the freeze-dried preparation of the present invention is prepared by dissolving a carbapenem antibiotic, a saccharide, and optionally an inorganic salt in an appropriate aqueous solvent such as distilled water for injection or physiological saline to prepare an aqueous solution, and sterilizing the aqueous solution. It can also be produced by filtration and lyophilization by a conventional method. A freeze-dried preparation produced by such a production method is a preferred embodiment of the present invention.

In the above-mentioned production method, the pH of the aqueous solution is adjusted to pH 3 to 7, preferably 4 to 6 by using an inorganic acid such as hydrochloric acid, an organic acid such as acetic acid, citric acid, tartaric acid, or sodium hydroxide.
It is preferable to adjust In addition, if necessary, stabilizers, antioxidants, pH regulators, solubilizers, buffers, and / or
Alternatively, formulation additives available to those skilled in the art, such as an isotonicity agent, may be added and lyophilized. Although the lyophilized preparation of the present invention can be used as it is, it is usually preferable to fill a vial or ampoule with a lyophilized preparation containing a fixed amount, preferably a unit dose of the active ingredient, and seal it for clinical use. . The freeze-dried preparation of the present invention can also be produced by dispensing a fixed amount of an aqueous solution containing a carbapenem antibiotic, a saccharide and optionally an inorganic salt into a vial or ampoule and subjecting the vial or ampoule to freeze-drying. be able to. These lyophilized preparations can be easily dissolved by adding an injectable solution such as distilled water for injection and stirring at the time of use.

[0012]

[Examples] Active ingredients (1R, 5S, 6S, 8R, 2'S, 4'S) -2-
((2-((4-((2S) -5-amino-2-hydroxypentanoyl)
Piperazin-1-yl) carbonyl) pyrrolidin-4-yl) thio) -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid hydrochloride, maltose, inositol, and sodium chloride are shown in Table 1 below. The active ingredient was dissolved in water to a concentration of 1% W / V, the pH was adjusted to 5.5 with acetic acid and sodium hydroxide solution, and freeze-dried by a conventional method to give a freeze-dried preparation. Was prepared.
This freeze-dried preparation was stored at 60 ° C., and the residual ratio of the active ingredient when stored for 5 days and when stored for 10 days was determined under the following conditions and expressed as a ratio with the amount of the active ingredient before storage. At the same time, preparations of Comparative Examples were produced and their stability was compared with that of the present invention. The results are shown in Table 1. The preparation of the present invention (No. 8 and
It is clear that 9) has a higher residual rate than the preparations of Comparative Examples.

Method of Analyzing Active Ingredients HPLC was used for measurement under the following conditions. Toyo Soda TSKgel ODS (4.6 × 150 mm) was used as a column, and the column temperature was room temperature. 1.2 ml of 0.05 M sodium acetate buffer (pH 4.0) containing 4% acetonitrile as mobile phase
Used at a flow rate of / min. Detection was performed by ultraviolet absorption at 299 nm. The injection volume was 50 μl and the injection sample concentration was approximately 50
It was set to around μg / ml.

[0014]

[Table 1] ──────────────────────────────────── Effective additive amount (mg) 60 ℃ 5 Day 60 ° C 10 days Drug composition ────────────── Operation Abuse Abuse No. (mg) NaCl Maltose Inosit Residual rate (%) Residual rate (%) ────── ────────────────────────────── 1 500---Powder subdivision 56.3 23.3 2 500---Freeze-dried 48.0 40.2 3 500 50--Freeze dry 32.0 21.4 4 500-500-Freeze dry 59.0 46.1 5 500--100 Freeze dry 71.9 64.2 6 500 50 500-Freeze dry 79.5 66.6 7 500 50-100 Freeze dry 0 0 8 500 50 300 100 Freeze dry 96.6 91.1 9 500 100 300 100 Freeze-dried 90.2 87.1 ─────────────────────────────────────

[0015]

The freeze-dried preparation of the present invention has higher storage stability than the conventional freeze-dried preparation, and the potency of the active ingredient does not decrease even after long-term storage. In addition, it is a useful formulation because it dissolves quickly by adding an injection solution or the like at the time of use.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 47/26 A61K 9/14 E // C07D 477/00 9271-4C C07D 487/04 134

Claims (8)

[Claims] 1. A carbapenem antibiotic or a salt thereof and 2.
A freeze-dried preparation containing at least one kind of sugar. 2. The freeze-dried preparation according to claim 1, which further contains an inorganic salt. 3. The freeze-dried preparation according to claim 1, wherein the sugars are inositol and mannitol. 4. A carbapenem antibiotic is represented by the following formula: [R ¹ represents a lower alkyl group or a hydroxy lower alkyl group which may have a protecting group; R ² represents a hydrogen atom or a lower alkyl group; R ³ represents a carboxyl group which may be esterified; R ⁴ represents an amino-protecting group, a hydrogen atom or a lower alkyl group; R ⁵ and R ⁶ each independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a hydroxy lower alkyl group or a halogen atom, and further R ⁵ and R ⁶ may combine with each other to form an alkylene group having 2 to 6 carbon atoms; R ⁷ is a hydrogen atom, a lower alkyl group, a carboxyl group, a carbamoyl group, a carboxyl group which may have a protecting group or a partial structure -CONR ⁷¹ R ⁷² (R ⁷¹ and R ⁷² each independently represent a hydrogen atom or a lower alkyl group) a; R ⁸ is a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl Represents a group, further R ⁷ and R ⁸ form an alkylene group may be 2 to 6 carbon atoms together; protecting group for an amino group are each R ⁹ and R ¹⁰ independently represent a hydrogen atom or a lower alkyl Group, Z is a single bond, an oxygen atom, a sulfur atom, or a partial structure: -CR ¹¹ R ^{12
-, -NR 13 CO -, -} CONR 14 or -NR ^15, - (R ¹¹ and
R ^12's each independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a hydroxy lower alkyl group or a halogen atom, and R ¹¹ and R ¹² are taken together and have 2 to 6 carbon atoms.
R ¹³ and R ¹⁴ each independently represent a hydrogen atom or a lower alkyl group,
¹⁵ represents an amino-protecting group, a hydrogen atom or a lower alkyl group); and m and n are each independently 0 to 6
The lyophilized preparation according to any one of claims 1 to 3, which is a compound represented by the formula] or a salt thereof. 5. A carbapenem antibiotic (1R, 5S, 6S, 8
R, 2'S, 4'S) -2-((2-((4-((2S) -5-amino-2-hydroxypentanoyl) piperazin-1-yl) carbonyl) pyrrolidin-4-yl) thio) -6 The freeze-dried preparation according to claim 4, which is-(1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid or a salt thereof. 6. A carbapenem antibiotic (1R, 5S, 6S, 8
R, 2'S, 4'S) -2-((2-((4-((2S) -5-amino-2-hydroxypentanoyl) piperazin-1-yl) carbonyl) pyrrolidin-4-yl) thio) -6 6. The compound is-(1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid hydrochloride.
The freeze-dried preparation according to. 7. A method for producing a freeze-dried preparation, which comprises freeze-drying an aqueous solution of a carbapenem antibiotic or a salt thereof in the presence of two or more kinds of sugars. 8. The method according to claim 7, further comprising freeze-drying in the presence of inorganic salts.